JP7189281B2 - System and method for cryogenic testing of closed container integrity - Google Patents

Description

This application claims priority to U.S. Provisional Patent Application No. 62/771,664, filed November 27, 2018, the entire disclosure of which is incorporated herein by reference. there is

The present invention is directed to systems and methods for cryogenically testing the integrity of closures of containers such as bottles, cartridges, syringes and the like.

The integrity of the seal between the container and the closure is a consideration when choosing packaging components for biological substances and pharmaceuticals. These substances are usually stored in glass or plastic containers (eg, glass vials, plastic vials, or syringes) capped with elastomeric closures. These substances include, for example, blood, serum, proteins, peptides, stem cells, DNA, other perishable fluids of biological origin, and freeze-dried or freeze-dried drugs.

The container must be able to protect these materials from various possible sources of contamination, including microbial ingress, moisture, and gas exchange. Therefore, the effectiveness of the closure of a container is often tested for the purpose of ascertaining the integrity of the closure (CCI) of the container. CCI is the ability of a container closure system to protect and maintain the potency and sterility of a substance, especially a drug, throughout its shelf life. The ability of elastomeric sealing components (eg, stoppers) to prevent the ingress of microorganisms into drug containers is verified by container closure integrity testing (CCIT). CCIT measures the integrity of the seal between the closure and the container.

A primary sealing area is formed at the interface between the elastomeric sealing component and the container. Assuming that the individual packaging components are free of defects, this joint is typically the primary source of possible failures in packaging. In order to ensure a satisfactory level of container closure integrity, a number of conditions must be considered in selecting and applying a drug-appropriate container closure system.

Manufacturing defects, such as misassembly, insufficient or excessive crimping force, or design errors, can compromise the integrity of the container closure system. Therefore, it is imperative to ensure that the elastomeric seal member is properly sized to the container to adequately establish the integrity of the seal. Reduced vacuum, gas ingress and exchange, pH adjustment, and contamination can compromise seal integrity, compromise drug sterility, affect drug efficacy, and potentially endanger patients. can increase

With the increasing preference for value-added bio-based products and pharmaceuticals, there is an increasing need for reliable container closure systems. Such bio-based products and drugs are typically temperature sensitive and can greatly deteriorate if not stored under proper conditions. It is not uncommon for some biological products and drugs to be stored in sealed containers at temperatures as low as -80°C, e.g., to avoid degradation or evaporative loss; 150°C or less) is often stored.

As noted above, most drug containers have elastomer seals. A physical property common to all elastomers is the temperature at which they lose their elasticity and change to a hard, glass-like state. This temperature is known as the glass transition temperature (Tg). In a room temperature environment, the thermal motion of molecules is in a steady state and the configuration of molecules is constantly changing, giving rise to flexibility and thus the ability to form a sealing area on another surface. However, at the glass transition temperature the mobility of molecules is greatly reduced, making the material brittle and glass-like. For example, a common glass transition temperature for butyl rubber is around -65°C. As a result, elastomeric sealing components may not maintain occlusive integrity at cryogenic temperatures, potentially compromising the sterility of the biological product or drug stored within the container. However, if the biological product or drug is to be stored at cryogenic temperatures, the integrity of the container closure should be established under these conditions.

Therefore, to ensure the integrity of the closure of a sealed container under conditions to which the contents of the container may be exposed, it is necessary to maintain the integrity of the closure of the container, particularly at temperatures below about -150°C, and even at about -180°C. It would be desirable to provide a system and method for inspecting sealed containers at cryogenic temperatures and below to ensure that the stopper or closure is effective in completely sealing the opening. It may also be desirable to ensure that the stopper or closure is effective in completely sealing the opening of the container at temperatures below about -196°C.

The present invention, in one embodiment, relates to a system for cryogenically testing the integrity of the closure of a sealed container. The system includes a sealed container, a cryogenic storage container, hollow tubes, fixtures, and leak detection equipment. The sealed container contains helium and includes an opening sealed by an obturator. The cryogenic storage vessel is at least partially filled with a cryogenic fluid and includes a first end and an opposite second end. An opening is provided at the first end. A hollow tube extends through the opening of the cryogenic storage container and has a first end located outside the cryogenic storage container and a second end located opposite the cryogenic storage container and located inside the cryogenic storage container. including ends. The jig includes a first end and an opposite second end. The second end is configured to fit in a sealed container. The jig is configured to be removably inserted into the hollow tube through the opening at the first end of the hollow tube to position the sealed container at or near the second end of the hollow tube. It is A leak detection device is connected to the hollow tube.

Another embodiment of the invention relates to a method of cryogenically testing the integrity of the closure of a sealed container. This method comprises the following steps. Providing a sealed container containing helium. Providing a cryogenic storage vessel having an open first end and an opposite second end at least partially filled with a cryogenic fluid. A hollow tube is placed in the opening of the cryogenic storage container such that a first end of the hollow tube is outside the cryogenic storage container and a second opposite end of the hollow tube is cryogenic. Placing under the interface of the cryogenic fluid inside the storage container. Securing the sealed container to the tip of the jig. Inserting a jig into the hollow tube to place the sealed container at or near the second end of the hollow tube. Connecting the hollow tube to a leak detection device to measure the flow rate of helium escaping from the cryogenic sealed vessel.

Another embodiment of the invention relates to a method of cryogenically testing the integrity of the closure of a sealed container. The method comprises providing a sealed container by the following steps. Inserting an elastomeric stopper into the opening of the container. threading the body of the elastomeric plug through the first opening and the second opening; Connecting the first conduit to the first opening by fitting the first end of the first conduit into the first opening and fitting the second end of the first conduit to a source of helium. connecting the second conduit to the second opening by fitting the first end of the second conduit into the second opening; Replacing air in the container with helium by supplying helium into the container through the first conduit and evacuating the air from the container through the second conduit. removing the first conduit from the first opening and removing the second conduit from the second opening; Covering the first opening and the second opening with a cyanoacrylate adhesive and allowing the cyanoacrylate adhesive to cure over a period of time to form a sealed container. The method further includes providing a cryogenic storage container at least partially filled with a cryogenic fluid, placing the sealed container within the cryogenic storage container, and connecting to the cryogenic storage container. measuring the flow rate of helium escaping from the cryogenic sealed vessel using a leak detection device.

The foregoing summary may be better understood when read in conjunction with the accompanying drawings in conjunction with the detailed description of the invention that follows. These drawings show presently preferred embodiments for the purpose of illustrating the invention. It should be understood, however, that the invention is not limited to the details of the arrangements and instrumentalities shown.

1 is a cross-sectional view of a conventional sealed container utilized in accordance with certain embodiments of the present invention; FIG. 1 is a perspective view of a coupler, one of the components of an inspection system according to an embodiment of the invention; FIG. FIG. 10 illustrates a mechanism for securing a sealed bottle during inspection, according to an embodiment of the present invention; 3B illustrates the mechanism of FIG. 3A; FIG. FIG. 10 illustrates a mechanism for securing a sealed bottle during inspection according to another embodiment of the present invention; 4B illustrates the mechanism of FIG. 4A; FIG. FIG. 10 illustrates a mechanism for securing a sealed bottle during inspection according to another embodiment of the present invention; Figure 5B illustrates the mechanism of Figure 5A; 1 is a perspective view of an inspection system according to an embodiment of the invention; FIG. 1 is a partially exploded perspective view of an inspection system according to an embodiment of the invention; FIG. 1 is a partially assembled perspective view of an inspection system according to an embodiment of the present invention; FIG.

Although certain terminology is used in the following description, it is for convenience only and is not intended to limit the invention. The terms "proximal", "distal", "upper", "lower", "bottom" and "upper" indicate directions in the drawings to which reference is made. The term "inwardly" means a direction towards the geometric center of the device according to the invention and certain parts thereof, and the term "outwardly" means a direction away from that center. Hereinafter, unless otherwise specified, the articles "a," "an," and "the" should be read as meaning "at least one" rather than being limited to one element. These terms include the words above, as well as derivatives and words of similar origin.

Like reference numbers refer to like elements throughout the drawings. Referring in detail to the drawings, FIGS. 1-8 illustrate preferred embodiments of systems and methods for cryogenically testing the integrity of a closure of a container closed by a closure.

The term "obturator", as used hereinafter, means a device that seals the opening of a container, such as a plug, plunger, or stopper, i. includes the meaning of an instrument that forms a sealing area by pressing a substance of The term "container", as used hereinafter, is a sealable container utilized to contain a substance or a sealable retainer utilized to hold a substance, especially during processing, Or it includes the meaning of those exposed to extremely low temperatures while being stored. In addition, the term "container," as used below, includes vials, bottles, syringes, pre-filled injection devices, laboratory vessels, etc., whose openings are sealable with closures to keep the contents intact. may include the meaning of what is kept in It will be appreciated by those skilled in the art that the system/method according to the present invention can be used with both solid and solid containers.

Some embodiments of the present invention are performed at cryogenic temperatures. In particular, some are carried out at temperatures below about -80°C, preferably below about -150°C, more preferably below about -180°C, and most preferably below about -196°C. Many biological materials, such as blood, serum, proteins, peptides, stem cells, DNA, and other perishable materials, are cryogenically preserved for the purpose of maintaining their viability for extended periods of time. Such preservation methods include dry ice (sublimation point -78.5°C).

The present invention relates to systems and methods for assessing CCI of closed containers. More particularly, the present invention relates to a system and method for detecting helium leaks for the purpose of cryogenic CCI inspection of closed vessels. Quantitative results from helium leak detection are reproducible and have higher accuracy than qualitative results expressed as pass/fail.

FIG. 1 shows a conventional closed container that can be used with the inspection system and method according to the invention. Referring to Figure 1, a vial 10 containing a drug or formulation (not shown) is shown. Vial 10 has a neck 12 with an open end 12a surrounded by a generally annular flange 14. As shown in FIG. A closure or plug 20, particularly of elastomer, is placed at the open end 12a of the vial 10 to seal the vial 10. As shown in FIG. Plug 20 includes a flange 22 and a plug 24 extending downwardly from flange 22 . Plug 24 is inserted into the opening enclosed by neck 12 of vial 10 to seal the opening. Approximately in the center of plug 24 is cavity 26 . A first end of this cavity 26 is closed by a pierceable component such as a needle and is preferably located in the geometric center of the flange 22 . A second end of cavity 26 is open to allow fluid communication to and from the contents of vial 10 . Stopper 20 may be formed from a resilient material or elastomer known to be suitable for pharmaceutical applications. Vial 10 may be formed from glass, ceramics, or polymers known to be suitable for pharmaceutical applications.

In one embodiment, the testing method according to the present invention is performed after the vial 10 and the stopper 20 are assembled together as shown in FIG. will be 1, the vial 10 is prepared for use in the testing method and system of the present invention by first providing a first opening 16 and a second opening 18 in the stopper 20. . These openings 16, 18 are hereinafter also referred to as "puncture sites". Preferably, both openings 16, 18 are the same size. However, it will be appreciated that the two openings 16, 18 may be of different sizes. In one embodiment, these openings 16, 18 are provided in the geometric center of the flange 22 of the plug. However, it will be appreciated that these openings 16 , 18 may be formed anywhere on the flange 22 . Each opening 16 , 18 extends through the body of flange 22 and includes a first end 16 a , 18 a on top surface 22 a of flange 22 and a second end 16 b , 18 b on bottom surface 22 b of flange 22 . The second ends 16b, 18b communicate with the interior of the vial 10. As shown in FIG.

A conduit or tubing 28, 30 is installed or connected to each opening 16, 18, preferably its first end 16a, 18a. For example, each opening 16, 18 may have a needle installed or connected thereto. A first conduit 28 located in or connected to the first opening 16 serves to supply an inert gas, such as helium, to the interior of the sealed vial 10 . A second conduit 30 located in or connected to the second opening 18 functions as an exhaust port or escape tube that allows air to escape from the vial 10 to be replaced with inert gas. Prevent overpressure. Preferably, the inert gas filling of the vial 10 is of sufficient volume to ensure complete replacement of the air within the vial 10 . Preferably, the vial 10 is flushed with an inert gas whose volume is ten times the headspace of the vial 10 to ensure complete replacement of the air within the vial 10. The air in 10 is displaced. In a preferred embodiment, the air in the vial 10 is replaced with 100% pure helium having a volume ten times the headspace of the vial 10 to ensure complete replacement of the air in the vial 10. . The headspace (ie, the gas space above the drug interface) of vial 10 includes cavity 26 of stopper plug 24 . It should be noted that the volume of inert gas charged need not necessarily be ten times the headspace of the vial 10, but only large enough to ensure complete replacement of the air within the vial 10. Hopefully, it will be understood. Preferably, the helium filling process is performed at room temperature.

After the vial 10 is filled with helium as described above, the first conduit 28 is removed from the first opening 16 and the second conduit 30 is removed from the second opening 18 . Each opening 16,18 is then covered with a layer 29,31 of adhesive. The adhesive may be any substance configured to seal the openings 16,18. In one embodiment, the adhesive is an epoxy adhesive, particularly a fast curing epoxy adhesive, or an instant epoxy adhesive. Preferably, the epoxy adhesive contains bisphenol A diglycidyl ether resin. A preferred commercially available epoxy adhesive is Devcon® Part No. 14250. In another embodiment, the adhesive is a glue, especially a fast-curing or fast-setting glue. For example, the adhesive is a cyanoacrylic adhesive. After the layers or coatings 29, 31 of adhesive are applied to the first opening 16 and the second opening, respectively, the applied adhesive is allowed to stand for a predetermined period of time to cure. Preferably, the adhesive layers or coatings 29, 31 cure over a period of time to become sufficiently hard to seal the openings 16, 18, thereby sealing the vial 10. As shown in FIG. Curing times can range from a few seconds to several minutes depending on the type of adhesive used, and can be longer (eg about 1 hour) depending on the properties of the adhesive used.

The vial 10 is then crimped and/or capped over after the adhesive has cured. The vial 10 may be tested immediately or stored at a predetermined temperature, such as room temperature or cryogenic temperature, until ready for testing. Preferably, the sealed vial 10 is slowly cooled to a predetermined temperature, such as -80°C, prior to cryogenic testing.

Although the operation of preparing a vial 10 described above was directed to a single vial 10, it is understood that multiple vials 10 may be prepared as described above. Will. In this case, the inspection is performed individually for each vial 10, as explained below.

It will be appreciated that filling the vial 10 with helium does not necessarily have to be done in the process described above, but can be done in any process and system known for helium filling. .

For example, in another embodiment, the method according to the invention is performed before the vial 10 and the stopper 20 are assembled together and the lid is crimped and/or capped thereon. More specifically, prior to inserting stopper 20 into open end 12a of vial 10, an inert gas, such as helium, is passed through open end 12a of vial 10 in preparation for use of the testing method and system according to the present invention. is fed into the vial 10. Preferably, this feeding takes place at room temperature. After the vial 10 has been filled with a predetermined amount of inert gas (e.g., a 100% pure gas with a volume of 10 times the headspace of the vial 10 to ensure complete replacement of the air within the vial 10). After the air in the vial 10 has been replaced with helium, the stopper 20 is placed on the open end 12a of the vial 10 to seal the vial 10, and the lid is crimped over the sealed vial 10. The vial 10 may then be inspected immediately or stored at a predetermined temperature, such as room temperature or cryogenic temperature, until ready for inspection. Preferably, the sealed vial 10 is slowly cooled to a predetermined temperature, such as -80°C, prior to cryogenic testing.

In one embodiment for inspecting vials 10 prepared as described above, the system 60 shown in FIGS. 6-8 is used. System 60 includes reservoir 32 and leak detector 34 . Those skilled in the art will appreciate that the leak detector is in particular a mass spectrometer and that any known or commercially available mass spectrometer may be used. In one embodiment, storage container 32 is a vacuum flask (thermos flask) commonly known as a Dewar. Storage vessel 32 may contain a cryogenic or liquefied gas for temperature control. Such gases include, but are not limited to, liquid nitrogen, liquid oxygen, liquid hydrogen, liquid helium, and the like. Preferably, at least a portion of storage vessel 32 is filled with liquid nitrogen such that the internal temperature of storage vessel 32 is approximately -196°C. 3A and 7, for example, reservoir 32 has a first end 36 and an opposite second end 38 . An opening 40 is provided in the first end 36 . Of system 60 , a pipe or hollow tube 42 , such as a dip tube, extends through opening 40 of storage container 32 and is rigidly attached within storage container 32 . Hollow tube 42 may be configured to be removable from reservoir 32 or may be configured to be non-removable. The dimensions of hollow tube 42 may be adjusted to match the size of opening 40 of reservoir 32, if desired.

In one embodiment, as shown in FIG. 2, a coupler 54 is provided to facilitate securing the hollow tube 42 to the opening 40 . Coupler 54 is preferably generally cylindrical in body and is sized and shaped to fit securely within opening 40 and surround hollow tube 42 . Coupler 54 may particularly be in the form of a plurality of cylindrical sections having different outer diameters, as shown in FIG. 2, or may be in the form of a tube having a uniform outer diameter along its entire length. good. In some embodiments, an adhesive may be used to secure coupler 54 to opening 40 . In another embodiment, coupler 54 is secured to opening 40 with an interference fit. Coupler 54 also has a circular hole 56 through its body. Because hole 56 is sized and shaped to receive hollow tube 42 therein, coupler 54 further stabilizes hollow tube 42 within opening 40 of storage container 32. be able to. Coupler 54 is further preferably provided with at least one vent or opening 58 for exhausting gas contained in reservoir 32 . In particular, since the liquid nitrogen constantly generates gas and pressurizes the interior of the storage container 32, the vent 58 of the coupler 54 is configured to exhaust the generated gas. It will be appreciated that coupler 54 may be provided with more than one exhaust port 58 .

Referring to FIG. 7, the above system may include an adapter 43 in addition to hollow tube 42 . Adapter 43 may be configured as a T-joint and removably connected to one end of hollow tube 42 . The connection is preferably secured with a mechanical connector 62, such as a clamp. The hollow tube 42 and the adapter 43 may be made of metal or plastic. Preferably, hollow tube 42 and adapter 43 are made of metal such as stainless steel. The hollow tube 42 has a first end connected to the adapter 43 and an opposite second end 45, the first end being configured to be positioned outside the reservoir 32, The two ends 45 are configured to be placed inside the reservoir 32 . The second end 45 is specifically positioned below the liquid nitrogen interface within the reservoir 32 . Adapter 43 includes a first leg 64 on one side of the tee and a second leg 66 attached to hollow tube 42 on the opposite side. Preferably those legs 44, 46 are in the form of hollow tubes or pipes. First leg 64 preferably includes an open end configured to be closed with cap 70 . This will be explained in more detail later.

Alternatively, the system may only include adapters configured as T-joints. In this case, the first leg and the second leg of the adapter are constituted by one hollow tube, the first open end of which corresponds to the first open end of the first leg 64 of the adapter 43, and the second end of which corresponds to the first open end of the first leg 64 of the adapter 43. It corresponds to the second end 45 of the hollow tube 42 . The mechanical connector 62 is not required when the system is assembled in this manner.

Hollow tube 42 is connected to mass spectrometer 34 through adapter 43 and conduit 49 (see FIGS. 6 and 8). Specifically, conduit 49 is removably connected to third leg 68 of adapter 43 (the leg perpendicular to first leg 64 and second leg 66). Third leg 68 is preferably shaped as a hollow tube or pipe. A conduit 49 connects hollow tube 42 to mass spectrometer 34 and provides a fluid passageway. As shown in FIG. 6, a first end 72 of conduit 49 may be removably connected to adapter 43 by another mechanical connector 51 (e.g., a clamp), and an opposite second end 53 may be attached to the mass. It may be connected to analyzer 34 . Mass spectrometer 34 is preferably a helium mass spectrometer. Preferably, the mass spectrometer 34 is calibrated against traceable standards for leaks established by NIST (National Institute of Standards and Technology) before being utilized to test vials 10 .

In one embodiment, system 60 further includes jig 46 housed within hollow tube 42 . Jig 46 is specifically configured to be removably inserted into adapter 43 and hollow tube 42 through the open end of first leg 64 of adapter 43 after cap 70 has been removed. Cap 70 may be removably attached to the end of first leg 64 by means well known to those skilled in the art. That means is preferably a clamp 44 . In another embodiment, cap 70 may be screwed onto the end of first leg 64 . Jig 46 is a rod, tube, or wire configured to retain sealed vial 10 within hollow tube 42 when the vial 10 is placed within storage container 32 for inspection purposes. It can be anything. The jig 46 has a first end 47 and an opposite second end 50 . Second end 50 is configured to hook onto or retain vial 10 in a sealed vial 10 .

In some embodiments, second end 50 of jig 46 includes or is shaped as a container or cavity configured to receive vial 10 . The vial 10 when received at the second end 50 is particularly sealed and filled with helium therein. For example, the second end 50 may include a cup-shaped container (not shown) that is sized and shaped to accommodate the sealed vial 10 during inspection of the vial. may have been

In another example, as shown in FIGS. 3A-3B, jig 46 is formed of flexible metal wire. In testing a sealed vial 10 , the second end 50 of the jig 46 is wrapped around or coiled around the vial 10 to secure the vial 10 .

In another example, as shown in FIGS. 4A-4B, jig 46 is formed of flexible plastic (eg, Nylon.RTM.) wire or rope. For inspection of the sealed vial 10, the second end 50 of the jig 46 is tied or secured around the vial 10, particularly its neck 12, to lower the vial 10 into the storage container 32 and secure it. do.

In another example, as shown in FIGS. 5A-5B, jig 46 is formed of a tube (metal or plastic) with second end 50 having a plurality of fingers or claws. and a locking mechanism 60 . Upon inspection of a sealed vial 10 , the fingers or nails of the securing mechanism 60 grip a portion of the vial 10 to secure the vial 10 .

FIGS. 3A-5B show a particular example of jig 46, particularly a mechanism provided at second end 50 of jig 46 for securing sealed vial 10. FIG. However, any form of jig 46 and mechanism provided at its second end 50 can lower and secure the sealed vial 10 into the storage container 32 for inspection purposes. It will be understood by those skilled in the art that it may be

In carrying out the testing method according to the present invention, a hollow tube 42 is attached to the opening 40 of the reservoir 32 and a coupler 54 is rigidly attached to the opening 40 . This places the second end 45 of the hollow tube 42 inside the reservoir 32 and below the interface of the liquid nitrogen, and places the first end of the hollow tube 42 outside the reservoir 32 and connects it to the adapter 43 . be done. A helium-filled and sealed vial 10 is then preferably prepared as described above and secured to the second end 50 of the jig 46 . A jig 46 is then inserted through the open end of the first leg 64 of the adapter 43 into the hollow tube 42 toward its second end 45 to position the vial 10 at or near the second end 45 . This causes the vial 10 and the drug therein to be cryogenically cooled. In one embodiment, the first end 47 of jig 46 is secured to first leg 64 of adapter 43 and the open end of first leg 64 is then closed with cap 70 and clamp 44 . In another embodiment, first end 47 of jig 46 may be secured to or integrally formed with cap 70 configured to close the open end of first leg 64 of adapter 43 . may have been In such an embodiment, cap 70 is first grasped and moved to insert jig 46 through adapter 43 and hollow tube 42 through the open end of first leg 64 of adapter 43 and then cap 70 is moved. may be placed at the open end of the first leg 64 to close the open end.

In another embodiment (not shown), storage vessel 32 may be omitted by incorporating a cooling system into fixture 46 . For example, in one embodiment, a jacket or coil surrounding the vial 10 may be provided at the second end of the jig 46 in which the vial 10 is placed. A liquefied gas (eg, liquid nitrogen) is flowed through this jacket or coil to cool the vial 10 to cryogenic temperatures. In another embodiment, adapter 43 and/or hollow tube 42 may be provided with a jacket or coil through which liquefied gas or other coolant flows.

It will be appreciated that the temperature in the storage container 32 may vary depending on the cryogen used. The internal temperature of storage vessel 32 is preferably less than or equal to about -150°C, more preferably less than or equal to about -180°C, and most preferably less than or equal to about -196°C (ie, the boiling point of liquid nitrogen).

After the sealed vial 10 is secured within the reservoir 32 as described above, operation of the mass spectrometer 34 begins. A mass spectrometer 34 places the vial 10 in a vacuum and measures the helium escaping from the vial 10 at cryogenic temperatures, preferably -196°C. The mass spectrometer 34 measures the partial pressure of helium within the leak detector and this "leak" from the vial 10 is (quantitatively measured and displayed) as a leak rate. After the leak rate is determined, the vial 10 can be warmed to room temperature. The concentration of helium in vial 10 is then measured using a calibrated headspace analysis probe (not shown) to determine the amount of helium remaining in vial 10 . The helium concentration and leak rate measurements are then used to calculate the actual helium leak rate (cc/sec) in the vial 10 . This leak rate is related to the size of the leak through which the helium escaped.

For −180° C. vials prepared in accordance with certain embodiments of the present invention, helium leak rates averaged on the order of E-9 to E-10 (ie, 10 ⁻⁹ to 10 ⁻¹⁰ ) std·cc/sec. be. By comparison, similar vials filled with helium at room temperature have leak rates in the range of E-7 to E-8 (ie, 10 ⁻⁷ to 10 ⁻⁸ ) std·cc/sec. Thus, there is a significant drop in leak rate measured according to embodiments of the present invention when room temperature samples are compared to samples tested at -180°C.

Although the following description relates primarily to vials, containers covered by the present invention include syringes, cartridges, blister packs, etc., and any container suitable for the storage or containment of biological products or drugs. will be understood.

It will also be appreciated that other gases may be used in systems/methods according to the present invention, depending on the type of analyzer utilized to detect the gas filling the headspace of the container. . Such analyzers include, but are not limited to gas chromatograph mass spectrometers (GC/MS) and emission spectrometers.
[Experimental example]

A total of 80 vials were tested at −180° C. with control samples using the system and method according to one embodiment of the present invention. These vials had either 2 mL or 10 mL capacity and were formed of a cyclic olefin polymer material (Crystal Zenith® (also referred to as CZ) manufactured by Daikyo Seiko). The obturator was a 13 mm or 20 mm halobutyl rubber stopper. All vials were prepared in hermetically sealed conditions as described above (i.e., all vials of samples, positive controls, and negative controls were filled with helium to replace the air in each vial with helium) and crimped. closed by a lid. The vials were then individually cryogenically tested (eg -180°C) and the helium leak rate from each vial was determined.

In particular, after a helium mass spectrometer (SIMS 1284+ Seal Monitoring System manufactured by Leak Detection Associates) has been calibrated to confirm system suitability, i.e. calibration is valid, each vial is tested for helium leaks. It was placed in a storage container or dewar for inspection. The reservoirs were for testing 2 mL and 10 mL vials respectively and were attached to a helium mass spectrometer. The temperature of the sample was maintained at −180° C. throughout while it was checked for helium leaks. A helium mass spectrometer pulled a vacuum around the sample and quantified the leak rate in units of std·cc/sec. If the analyzer was unable to create a vacuum around the sample, it was identified as a "severe leak". The above process was performed on both the 2 mL vial and the 10 mL vial.

Testing was performed on 5 identical positive controls, ie vials with 2 μm holes in the body, along with 20 new vials per day. Evaluation of the above treatments was performed by a first inspector and a second inspector. A first reviewer tested the above process for precision, robustness, specificity, and limit of detection (MDL), and a second reviewer tested it for intermediate precision (within-laboratory reproducibility). The results of the inspections by the first inspector and the second inspector are given in Tables 1-4. The criteria for a good sample was a leak rate of 1.9×E−6 (ie, 1.9×10 ⁻⁶ ) std·cc/sec or less.
-accuracy-

On day 1 (day 1), 5 2 μm positive controls and 20 samples were tested using the system and method described above. The results are shown in Table 1. "MHLR" represents the measured helium leak rate, ie, the leak rate determined by inspection in vacuum and not corrected for helium concentration.
- Intermediate precision -

On the second day (day 2), a second inspector uses the system 60 and method according to the present invention in the same procedure, with the same positive control as the first inspector and 20 different container samples. , tested on different helium mass spectrometers. The results are shown in Table 1.
- Specificity, MDL, Robustness to Analyzer, Robustness to Sample Type -

On day 3 (day 3), a first examiner tested the same positive control using the same procedure with the system and method according to the present invention. The results are shown in Table 1.

Robustness to sample type was tested by testing 2 mL container samples. The results are shown in Table 2.

Specificity was determined by confirming whether the analyzer was able to detect and distinguish between good and bad containers. The lower limit of detection was verified to be 2 μm.

Robustness to the analyzer was also tested and confirmed by testing with the data collection time set to 50 seconds and 70 seconds in addition to the scheduled 60 seconds. The results show that the analyzer is robust enough in its performance to give the desired results even when possible variations in data collection are taken into account. These results are shown in Tables 3 and 4.

All vial samples tested according to the present invention met the criteria of a leak rate of less than or equal to 1.9×E-6 (ie, 1.9×10 ⁻⁶ ) std·cc/sec. On the other hand, the positive control had a leak rate exceeding 1.9×E-6 std·cc/sec.

（２３５２８５、２３５２９１、２３５２９５、２３５３０１、２３５３０３はそれぞれ陽性対照１、２、３、４、５を表す。）

(235285, 235291, 235295, 235301, 235303 represent positive controls 1, 2, 3, 4, 5, respectively.)

It will be appreciated by those skilled in the art that changes may be made to the above-described embodiments without departing from the broad concepts of the invention. It is therefore intended that this invention not be limited to the particular embodiments disclosed, but that modifications be made within the spirit and scope of the invention as defined by the appended claims. I understand what you mean.

Claims (6)

A method of cryogenically testing the integrity of the closure of a sealed container comprising:
providing a sealed container;
providing a cryogenic storage vessel at least partially filled with a cryogenic fluid;
placing a sealed container in the cryogenic storage container;
measuring the flow rate of helium escaping from the cryogenic sealed container using a leak detection device connected to the cryogenic storage container;
The step of providing the sealed container comprises:
inserting an elastomeric stopper into the opening of the container;
passing a first opening and a second opening through the body of the elastomeric plug;
connecting the first conduit to the first opening by fitting the first end of the first conduit into the first opening and fitting the second end of the first conduit to a source of helium;
connecting the second conduit to the second opening by fitting a first end of the second conduit into the second opening;
replacing air in the container with helium by supplying helium into the container through the first conduit and escaping air from the container through the second conduit;
removing the first conduit from the first opening and removing the second conduit from the second opening;
covering the first opening and the second opening with a cyanoacrylate adhesive and allowing the cyanoacrylate adhesive to cure over a period of time to form the sealed container. placing a hollow tube through an opening of the cryogenic storage vessel with a first end of the hollow tube outside the cryogenic storage vessel and an opposite second end of the hollow tube; inside the cryogenic storage container and below the interface of the cryogenic fluid;
fixing the sealed container to a tip of a jig;
2. The method of claim 1, further comprising inserting the jig into the hollow tube to position the sealed container at or near a second end of the hollow tube. The method of claim 1, wherein said cryogenic temperature is about -150°C or less. 2. The method of claim 1, wherein said cryogenic fluid is liquid nitrogen. 2. The method of claim 1, wherein said cryogenic storage vessel is a Dewar. 2. The method of claim 1, wherein said leak detection device is a helium mass spectrometer.

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